Citations

Abstract Heat shock protein (HSP) 90 is a molecular chaperone that modulates stability of several client proteins, many of which are key regulators of signaling pathways in glioblastoma multiforme (GBM). The potential for targeting multiple effectors makes HSP90 an appealing therapeutic target for GBM. The biological activity of HSP990, a novel HSP90 inhibitor (Novartis Pharmaceuticals) as single agent was evaluated in a panel of short-term explant cultures derived from primary GBM xenografts (n=10). HSP990 treatment resulted in a dose-dependent growth inhibition in the all xenograft lines, with an IC50 ranging from 5 to 30 nM. A 72 h exposure to HSP990 (10–30 nM) resulted in a dose-dependent decrease in the HSP90 client proteins Akt, Cdc2 and Cdc25C, a decrease in associated post-translational modifications p-Akt (S473), p-CDC2 (Y15), p-CDC25 (S216), and increased expression of HSP70. Additionally, a dose-dependent increase in HSP990-induced apoptosis (Annexin-V positivity), was observed within 24–72 hours of drug treatment. GBM tumors harbor a subpopulation of glioma stem cells that grow as neurospheres in neurobasal media and are considered important for tumor maintenance and progression. The effects of HSP990 were tested in neurospheres derived from 4 of the xenografts tested above (GBM12, GBM39, GB59, GBM12TMZ). These cultures demonstrated potential for tri-lineage differentiation upon serum challenge and had robust secondary neurosphere formation, demonstrating two hallmark features of cancer stem cells. In a bulk-culture neurosphere formation assay, co-incubation with 5 to 10 nM HSP990 was highly effective at suppressing neurosphere formation in all 4 xenograft lines. Notably, in GBM12 neurosphere cultures maintained in either serum-free media or challenged with serum, 30 nM HSP990 was equally effective at promoting up-regulation of HSP70, but exhibited less effect on Akt or Cdc2 in serum-free cultures as compared to cultures supplemented with serum. Incubation of serum-free neurosphere cultures with 5 nM HSP990 (5 days) resulted in increased glioneuronal differentiation exhibiting elevated GFAP, Oct-4 and beta-tubulin expression compared to untreated controls. To test ‘self renewal’ GBM12 neurospheres were treated with HSP990 (10, 30 nM) for 7 days followed by dissociation and plating equal numbers of viable cells at low density in fresh drug-free neurobasal media. Interestingly, HSP990 treatment did not affect the number of secondary neurospheres (surviving fraction: control = 1.00, 10 nM = 1.30, 30 nM = 1.05). Treatment of GBM12TMZ flank tumor xenografts with weekly HSP990 (13 mg/kg P.O.) resulted in a modest 9 day delay in tumor re-growth (40.3 and 49.3 respectively) compared to placebo treatment. In conclusion, HSP990 (a) had anti-proliferative, pro-apoptotic effect on differentiated serum-supplemented xenograft cultures (b) a pro-differentiation effect on serum-free GBM stem cell cultures (c) markedly suppressed neurosphere formation with prolonged drug exposure but not with more limited drug exposure (d) inhibited GBM growth in vivo. Thus, HSP990 may inhibit GBM growth both through direct growth inhibition and through pro-differentiation effects on GBM stem-like cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B100.

Background —Approximately 360 000 Americans experience sudden cardiac arrest each year; current treatments are expensive and not very effective. Public access defibrillation (PAD) is a novel treatment for out-of-hospital sudden cardiac arrest that refers to use of automated external defibrillators by the lay public or by nonmedical personnel such as police. A clinical trial has been proposed to evaluate the effectiveness of public access defibrillation, but it is unclear whether such early defibrillation will offer sufficient value for money. Our objective was to estimate the potential cost-effectiveness of public access defibrillation by use of decision analysis. Methods and Results —A decision model compared the potential cost-effectiveness of standard emergency medical services (EMS) systems with that of EMS supplemented by PAD. We considered defibrillation by lay responders or police, using an analysis with a US health-care perspective. Input data were derived from published data or fiscal databases. Future costs and effects were discounted at 3%. Monte Carlo simulation was performed to estimate the variability in the costs and effects of each program. Sensitivity analyses assessed the robustness of the results to changes in input data. A standard EMS system had a median cost of $5900 per cardiac arrest patient (interquartile range, IQR, $3200 to $10 900) and yielded a median of 0.25 quality-adjusted life years (IQR, 0.20 to 0.30). PAD by lay responders had a median incremental cost of $44 000 per additional quality-adjusted life year (IQR, $29 000 to $68 900). PAD by police had a median incremental cost of $27 200 per additional quality-adjusted life year (IQR, $15 700 to $47 800). The results were sensitive to changes in the cost and relative survival benefit of PAD. Conclusions —Although more expensive than standard EMS for sudden cardiac arrest, PAD may be economically attractive. The effectiveness and cost-effectiveness of PAD should be assessed in a randomized, controlled trial.

BACKGROUND In acute myocardial infarction, residual flow to the infarct zone either through antegrade flow in the infarct-related coronary artery or collateral flow from the non-infarct-related arteries is often present before reperfusion therapy. The purpose of this study was to assess the influence of antegrade flow in the infarct-related artery and/or collateral flow to the infarct zone before successful direct angioplasty on infarct size and myocardial salvage in patients with acute evolving myocardial infarction. METHODS AND RESULTS Sixty patients with acute evolving myocardial infarction underwent direct successful angioplasty without prior thrombolytic therapy. The myocardium at risk of infarction, the final infarct size, and myocardial salvage were measured by tomographic perfusion imaging with 99mTc sestamibi. Antegrade flow in the infarct-related artery before intervention was graded according to the Thrombolysis in Myocardial Infarction (TIMI) study group classification. Collateral flow to the infarct zone before angioplasty was also graded (0 through 3, 0 being no collateral flow). The presence of even minimal antegrade flow before angioplasty (TIMI grade 1) in the infarct-related artery compared with absent flow was associated with a significant reduction in final infarct size (9 +/- 17% versus 23 +/- 19% of left ventricle, P = .02) and a significant increase in myocardial salvage (23 +/- 16% versus 14 +/- 13% of left ventricle, P = .05) after angioplasty. When antegrade flow in the infarct-related artery was absent before angioplasty, the presence of collateral flow before angioplasty resulted in a significantly smaller final infarct size (P = .01) and more myocardial salvage (P = .05) after angioplasty. Both antegrade infarct-related artery flow and collateral flow to the infarct zone had significant independent ability to predict infarct size after angioplasty. When collateral grade and TIMI grade were added to provide an estimate of residual flow, a model including residual flow, myocardium at risk, and the interaction of residual flow and infarct site explained 83% of the variability in infarct size after angioplasty. CONCLUSIONS The presence of antegrade flow in the infarct-related artery and/or collateral flow to the infarct zone before direct angioplasty in acute evolving infarction results in a smaller infarct size after direct successful angioplasty.

BACKGROUND Patients who have chest pain without electrocardiographic ST elevation are not candidates for thrombolytic therapy in most clinical trials. This study examined the value of technetium-99m-Sestamibi tomographic imaging to assess myocardial perfusion in patients during chest pain without ST elevation. METHODS AND RESULTS Tc-99m-Sestamibi was injected in 14 patients who had chest pain without ST elevation, who subsequently developed enzymatic evidence of myocardial infarction within 24 hours. Tomographic imaging was performed 1-6 hours after injection. Thirteen of 14 patients showed significant perfusion defects indicative of acute myocardial infarction consistent with absent perfusion (20 +/- 15% of the left ventricle; range, 2-53%); one patient had normal images. Because of the absence of definitive electrocardiographic changes, only five patients received reperfusion therapy within 6 hours of the onset of chest pain. Regional wall motion abnormalities were present in nine of nine patients undergoing contrast ventriculography and correlated with the location of the Tc-99m-Sestamibi perfusion defect. At the time of subsequent coronary angiography, total arterial occlusion was present in 11 of the 14 patients. The infarct-related artery could be identified in 13 of the 14 patients. In six of these 13 patients, the left circumflex was the infarct-related artery. CONCLUSIONS Patients who have chest pain without electrocardiographic ST elevation may have arterial occlusion and significant myocardium at risk. Tc-99m-Sestamibi imaging may be of benefit in identifying these patients early so that they can be considered for acute reperfusion therapy.

This study attempts to bring into focus certain details which have not been described adequately in textbooks of anatomy. This information is now of considerable significance because of its role in the genesis and surgical treatment of mitral stenosis. Variations in the size and shape of the mitral valve are described, with particular reference to the fact that valve commissures, or junctional zones between the leaflets, occur in the normal valve. Measurements of commissures, chordae tendineae and valve leaflets are presented, with a discussion of the significance of some of these measurements.

Knowledge of the structural changes in the commissures, cusps, and chordae tendineae is important to the understanding of the pathologic physiology of mitral stenosis and its surgical correction. Study of 70 hearts with mitral stenosis disclosed that a frequent cause of the obstruction was commissural fusion or shortening of the chordae tendineae or both. In a small percentage of hearts, mitral stenosis appeared to result principally from rigidity of the valvular leaflets. Measurements of the various components of the mitral valve in normal hearts have been given in a previous paper. In this communication, comparable measurements for these structures in 50 hearts with mitral stenosis are presented.